1. Cyclic analogs of galanin and neuropeptide Y by hydrocarbon stapling
- Author
-
H. Steve White, Hee Kyoung Lee, Brian D. Klein, Brad R. Green, Misty D. Smith, and Grzegorz Bulaj
- Subjects
Male ,Agonist ,medicine.drug_class ,Stereochemistry ,medicine.medical_treatment ,Molecular Sequence Data ,Clinical Biochemistry ,Pharmaceutical Science ,Neuropeptide ,Galanin ,Biochemistry ,Protein Structure, Secondary ,Mice ,Epilepsy ,Drug Stability ,Drug Discovery ,medicine ,Animals ,Neuropeptide Y ,Amino Acid Sequence ,Receptor ,Molecular Biology ,Protein Stability ,Chemistry ,Organic Chemistry ,medicine.disease ,Neuropeptide Y receptor ,In vitro ,Rats ,Anticonvulsant ,Cyclization ,Molecular Medicine ,Anticonvulsants - Abstract
Hydrocarbon stapling is an effective strategy to stabilize the helical conformation of bioactive peptides. Here we describe application of stapling to anticonvulsant neuropeptides, galanin (GAL) and neuropeptide Y (NPY), that are implicated in modulating seizures in the brain. Dicarba bridges were rationally introduced into minimized analogs of GAL and NPY resulting in increased α-helical content, in vitro metabolic stability and n -octanol/water partitioning coefficient (log D ). The stapled analogs retained agonist activities towards their respective receptors and suppressed seizures in a mouse model of epilepsy.
- Published
- 2013